Therapeutic metal cevitamate compositions



Patented Sept. 23, 1947 THERAPEUTIC METAL CEVITAMATE COMPOSITIONS SimonL. Ruskin, New York, N. Y., assignor to Frances It. Ruskin No Drawing.Application July 29, 1940, Serial No. 348,295

6 Claims.

The present invention relates to the manufacture' of new preparationsfor use in human therapy and more particularly to a new and improvedmedium for the introduction of therapeutic metals into the animalorgans.

This application is a continuation-in-part of my prior applicationsSerial No. 745,527 filed September 26, 1934, which issued on October 28,1941, under No. 2,260,870; Serial No. 50,237, filed November 16, 1935,which issued on May 14, 1946, under No. 2,400,171, and Serial No.210,772, filed May 28, 1938, which issued on October 21, 1941, under No.2,259,492.

It is a general object of the invention to provide therapeuticpreparations containing metals in combinations which are highlyefflcient for their intended purposes, are non-toxic, in the indicateddosages, and can be administered parenterally without irritation andwithout danger of sloughing.

More specifically, it is an object of the invention to providepreparations for use in metal therapy in which the metal is combinedwith or associated with an organic radical which is a normal componentof the blood stream and of various tissues of the human body, whereby amore rapid and more normal absorption of the metal by the body isensured.

It is a further object of the invention to provide therapeuticpreparations composed in whole or in part of compounds containingtherapeutic metals which are distinguished over compounds of such metalsnow in general use by at least one of the following characteristics:greater compatibility with the components of the blood stream and of thetissues; reduced toxicity, greater solubility, greater absorbabilitywith resultant improved therapeutic eificiency, and fortifiedtherapeutic action of the metal by reason of thenature of the medium towhich it is chemically united or with which it is otherwise associated.

In accordance with the invention, the various metals now employed inchemotherapy are introduced into the human body, by injection or bymouth, with the aid of a medium in the form of the unsubstituted orsubstituted laevo-ascorbate or cevitamate radical, the metal beingassociated with such radical in any suitable and effective combination,being either directly combined with such radical in the form of a salt,or in the form of a base or of a salt of another acid associated orcompounded with unsubstituted or substituted cevitamic acid or with asalt of cevitamic acid.

be understood those metals whose compounds are employed in the field ofchemotherapy; that is, compounds which are administered internally,either by mouth or parenterally, for the treatment f various diseases orsystemic or functional disorders. A large number of these metals arereferred to hereinbelow; the enumeration of these metals is, however, tobe understood to be given solely by way of example and not as excludingother metals whose compounds have been used in human therapeutics. I

It is known that cevitamic acid, also known as "vitamin C," normally.occurs in the free condition in the human body. I have found that thisacid and certain derivatives thereof form salt or salt-like combinationswith metals and thereby yield therapeutic agencies for the introductionof such metals into the human system which are characterized by valuableand unsual properties. In addition to the therapeutic values imparted tothese products by the therapeutic metal itself, the compounds in generalhave also anti-scorbutic effects. possess anti-scorbutic action, was notto be expected in view of the fact that the vitamin occurred universallyas a free acid in fruits and vegetables and in the animal tissues; stillless was it to be expected that, as I have found, the cevitamate radicalwill enhance the therapeutic eificiency of the metal.

Thus in the case of calcium cevitamate, I have found over a long courseof clinical investigations that this compound increases the calciumcontent By therapeutic metals as employed in this specification and inthe appended claims are to of the blood much better than any othercalcium compound heretofore employed for calcium therapy. Calciumcevitamate is more readily absorbed and maintains the calcium content ata higher level than similar quantities of other calcium salts, thisbeing due in large part to the very high solubility and high degree ofionization of the salt. Compared with calcium gluconate, one of thesalts heretofore most commonly employed in calcium therapy, calciumcevitamate is far more soluble and hence can be used in more highlyconcentrated solution so that smaller volumes need be injected. Evenwhen used in strong solution, calcium cevitamate does not have anyirritating or other untoward effects on injection. I have found that inthe treatment of rickets, calcium cevitamate is more efiective thanother calcium salts and quickly gives evidence of more rapid clinicalimprovement. In the treatment of pyorrhea alveolaris, calcium cevitamatediminishes the tendency toward bleeding of the gums, stops the recessionof the alveolus from That the neutralized vitamin will still 7 the crownof the tooth and effects rapid improvement of this condition. Thiscalcium salt efiects also a more rapid deposit of calcium in toothformation; and it is, further, an active agent in strengthening thestructure of the blood vessels and in promoting clotting of the blood,thereby reducing hemorrhages.

Whereas, in the case of certain metal preparations heretofore employedin metal therapy. it was inadvisable to inject the preparationsotherwise than intravenously, the corresponding cevitamic acid compoundsof these metals can be injected not only intravenously but alsointramuscularly. Thus, calcium gluconate usually had to be employedintravenously because of the danger of producing sloughs; while calciumchloride could be injected only intravenously. Calcium cevitamate, onthe other hand, is not limited in the method of its administration andcan be repeatedly injected intramuscularly without danger of sloughing;This mode of injection is favored by the high solubility of calciumcevitamate. This compound is also exceptionallystable in the presence ofcarbon dioxide, phosphoric acid and other chemical substances in thehuman tissues with which calcium normally forms insoluble compounds.

A further and quite unexpected property of calcium cevitamate is thefact that the calcium and cevitamate portions of the compound show analmost completely parallel action in bone metabo1ism, hemorrhagicdiathesis, cell membrane permeability and detoxicating action.Investigations have indicated that the cevitamate radical is aphysiological carrier for calcium. This explains the remarkableparallelism in the physio logical behavior of the calcium cevitamateradicals. As further parallel actions may be mentioned and the fact thatboth increase the coagulability of the blood, inhibit allergicreactions. possess a detoxicating action on heavy metals and on arsenicand participate in tooth and bone growth. In fact, their actions inallergy are so alike as to make calcium cevitamate a double acting agentwherewith there is obtained an intensification of calcium actionhitherto unobtainable with other calcium compounds in similar dosage.Both ions have a similar physiological action on the vegetative nervoussystem and have shown favorable action in reducing diarrhea inintestinal tuberculosis. Similarity of action has been found also in anumber of other diseases showing a striking parallel action in twootherwise quite dissimilar ions. This parallel action indicates adefinite correlation; and further, that the cevitamic radical is astabilizing agent for calcium in the body and participates orfacilitates absorption and maintenance of the ionized calcium in serumcalcium.

Calcium cevitamate has proved to be highly effective in the treatment ofacute rhinitis. See Ruskin, "Annals of Otolgy, Rhinology andLaryngology, vol. 47, No. 2, page 502.

Recent research has shown that calcium cevitamate isabsorbed by theblood proteins and thus becomes available for use in the body metabolismto the extent of four times as much as calcium gluconate. In fact,researches with an improved Abbe refractometer have indicated thatcalcium cevitamate has a higher degree of re-activity with the bloodserum proteins than vitamin C itself.

In the case of the compounds bismuth, antimony and arsenic, hithertoemployed for the treatment of various diseases such as syphilis,-

and trypanosomiasis, the administration of these compounds hasfrequently been attended by irritation and even poisoning and sometimesgives rise to dermatitis, gingivitis, and other affections. While theseside effects are in certain cases due to the susceptibility of thepatients to bismuth, antimony and arsenic poisoning, they are frequentlydue, either entirely or in part, to the other constituents of themedicinal. It is my belief that the untoward eflects, or a great part ofthem, obtainecLwith the use of the known compounds of these metals can,to a great extent, be traced to the fact that the remainder of themolecule is just as foreign to the human organism, and particularly tothe blood stream, as the metal it is sought to introduce and just aspoisonous or diiiicultly tolerable, so that the system receives a doubleshock from both the therapeutic metal and the organic radical to whichit is joined. By combining these ordinarily toxic metals with thecevitamate radical, where necessary with the aid of sodium hydroxide,for solubilization, there is obtained, in accordance with the invention,compounds which are considerably less toxic and less irritating oninjection than the known compounds of these metals, while at the sametime a high therapeutic efliciency is maintained and the efliciency evenincreased. The cevitamate compounds of bismuth, antimony and arsenichave been found by me to .be more readily tolerated by the humanorganism and possess the property of inhibiting the tendency todermatitis, and gingivitis, frequently observed in bismuth, antimony andarsenic therapy. It appears that the peculiar structure of thecevitamate radical, which supplies both oxidation and reductionmechanisms, makes it an effective detoxicating agent; the administrationof the cevitamates of bismuth, antimonyand arsenic is thus attended withless danger and discomfort than heretofore. The oxidation-reductionproperties of the cevitamate radical also appear to increase theactivity of the metal, while at the same time reducing its toxicefiects.

I have found further that the cevitamic'acid compounds of bismuth,antimony and arsenic, in contrast to many of the organic compounds ofthese metals now employed in therapy, are quite soluble in water andwith the aid of a stabilizing agent, and particularly at a pH value ofabout 7.6 or slightly higher, can be kept indefinitely in solution. Likethe corresponding salt of calcium and also of other metals referred tohereinbelow, the cevitamates of bismuth, antimony and arsenic possessalso the physiological action of the free acid, and thus simultaneouslyact to correct morbid conditions arising from a deficiency of vitamin C.

The iron and copper compounds of cevitamic acid, prepared in accordancewith the invention, either individually or in combination, with orwithout the corresponding cobalt compound, have proved to be remarkablyeflicient and easily tolerated agents for the treatment of variousanemias, and particularly of nutritional anemias. They can beadministered by mouth and also parenterally andespeciallyintramuscularly, and without discomfort. Because of the highrate of absorption, considerably smaller dosages are required than ofhitherto employed medicinals for similar purposes. The administration ofiron, or ironcopper or iron-copper-cobalt cevitamates is relatively freefrom the gastric and intestinal disturbances which frequently accompanythe administration by mouth of known iron and copper compounds; and theyare also quite free of the disturbances both at the point of injectionand systemically, which frequently occur in the parenteral introductionof the known preparations. The efliciency of the known compound is quitelow and correspondingly large doses must therefore be employed. Thus,although the average daily requirement of iron to secure 1% hemoglobinuse is one-half grain, the dosage of iron ammonium citrate is 90 grainsper day. In the case of iron cevitamate, on the other hand, the dosageneed be only grains. Although cevitamic acid is a relatively unstablecompound and its salts were accordingly to be expected to be similarlyunstable, this relative instability, far from being a disadvantage inthe therapeutic preparations of the present invention, is in allprobability responsible, at least in large part, for the unusualeflicacy and efficiency of my new preparations, and particularly of theiron and copper compounds. This fact is closely associated with thecircumstance, referred to hereinabovc, that the cevitamic radical is anormal agency whereby metals and metallic compounds become combined withblood proteins and thereby become assimilable by the body tissues. Thesubstances utilized by the body must first be converted into a proteincomplex, and as I have found, the cevitamate radical has the uniquetendency toward the formation of protein complexes and thus improvesassimilation (see Ruskin, Studies on the parallel action of vitamin Cand calcium, American Journal of Digestive Diseases, vol. 5, page 408(1938); Ruskin, "Studies in calcium metabolism. Further contribution tocomparative studies of physical-chemical properties of gluconate andcevitamate of calcium and of vitamin C, Ibid., vol. 5, page 676 (1938)Ruskin I is likewise due to the fact that the cevitamate radical is anormally occurring substance in the human blood stream. As the metal andother ions forming part of the metal cevitamates are likewise normalconstituents of the blood stream, the metal cevitamates may be said torepresent substances indigenous to the blood stream and this accountsfor their easy toleration on injection and for their ready assimilationon oral administration.

According to this embodiment of the invention, therefore, thetherapeutic metals indicated in the treatment of anemias are introducedinto the animal organism in the form of their cevitamic acid compounds,either as simple salts of the acid or in more complex metal combinationswith the cevitamic acid radical, or with organic derivatives ofcevitamic acid. The anti-scorbutic action of these metal cevitamatesappears to be lower than that of free vitamin C; however, their vitaminC action is considerable and they are accordingly particularly indicatedin the treatment of nutritional anemias accompanied by scurvy. Thepatient is thus benefited not only by the As in the case of the othersupply of iron and the other anti-anemic metals,

of red blood corpuscles to a greater extent than any of these elementsalone. Thus, although copper will increase the eflicacy of iron in theelevation of the number of red blood corpuscles and the hemoglobincontent, the addition of cobalt will produce a still further increase.It will be noted that the iron compound is an organic ferrous salt, theiron being combined with an organic acid having reducing properties;this preparation is thus of a quite diiferent nature from the inorganiccompounds heretofore employed for the treatment of anemia. I

Unless otherwise indicated herein, the dosage of any particular metalcevitamate can correspond to the usual known dosage for the metal in theknown compounds, even where this will indicate a large excess of vitaminC radical over the normal body requirements. Contrary to early views, Ihave found that a large excess of vitamin C radical, at least incombination with therapeutic metals, has no deleterious effects in sofar as the dosage of the metal itself is within safe limits; in otherwords, there is practically no danger of an over-dose of the cevitamate.radical. In most instances, it will be found that, as indicated above,considerably smaller dosages of the various metals will be necessary inview of the greater efliciency of absorption of the metals in the formof the cevitamate compounds or complexes. Thus in the case of calciumcevitamate, a usual dose is 3 cc. of a 15% solution, injectedintramuscularly or subcutaneously. This represents a considerable excessof cevitamate radical over the normal daily vitamin C requirements(20-60 mg).

The compounds may be prepared in any of the known ways for themanufacture of metal salts, as by reacting free cevitamic acid with thehydroxide or carbonate of the metal. In certain cases, the sodium saltsof cevitamic acid may be reacted with a suitable salt, such as thechloride, of the metal whose cevitamate is to be formed. With certainmetals these reactions form precipitates i. e. compounds insoluble inwater and, in such case, the compounds may be brought into solution bysuitable'adjustment of the pH, as by the addition of sodium hydroxide toraise the pH above 7 but within limits still suitable for injection.With other compounds it may be necessary to add solubilizing agents likethe sugars, for ex-.

ample sucrose, calcium saccharate, and the like, where these arecompatible with the metal cevitamate. Excess of cevitamic acid may bepresent in certain cases, the reducing nature of such acid causing it toact as an anti-oxidant and stabilizer.

It is generally advisable, especially where the preparations aremarketed in the form of solutions, to include'suitable anti-oxidants orstabilizers in such solutions. Suitable stabilizers for the variouscevitamates, are the amines and amine derivatives, such as acetanilid,phenyl alanine, adrenalin, mono-, di-, and tri-ethanolamine and otheramido and imino compounds. Among the inorganic anti-oxidants, alkalimetal sulfites and metasulfites, such as the sodium compounds, may bementioned. In general, compounds having a reducing action are suitableforthis purpose provided that they are not toxic in the concentrationsand quantities employed. Only small proportions of these stablizers maybe employed, say up to several percent of the weight of the metalcevitamate. Various known buffer substances may be employed to maintainthe pH within more or less predetermined limits.

In most cases the reaction between the cevi- 7 tamic acid or its alkalimetal salt with the compound of the metal whose cevitamate is to beproduced takes place spontaneously without the application of heat orpressure. However, it is sometimes desirable to heat the reactionmixture moderately in order to render the reaction more complete. Thereactions are preferably conducted in an inert atmosphere, for example,of carbon dioxide or nitrogen; and pressure may be employed, especiallywhere the cevitamic acid is caused to react with a carbonate, so as tocause the solution of considerable amounts of carbon dioxide which aidin stabilizing certain of the salts, especially of calcium cevitamate.In the latter case the reaction should take place in the cold so as tokeep as much as possible of the carbon dioxide in solution. The wateremployed is preferably de-aerated, as by boiling or by passing a currentof an inert gas therethrough. Free oxygen destroys to a large degree thepotency of the cevitamates and for best results the process should becarried out in the absence of oxygen. The final product may be either asolution, which can be packaged in ampules, capsules, etc., preferablyin an inert gas, or in the form of a solid. obtained by evaporation ofthe solution to dryness, preferably with the aid of a vacuum. The solidmaterial can be prepared for the market in tablet form and the tabletsmay be coated with a soluble film which is impervious to air, forexample, a coating of gelatin.

The following examples set forth various embodiments of the inventionbut it will be understood that the same are presented by way ofillustration and not as indicating the limits of the invention:

Example 1 12.896 grams of laevo-ascorbic or cevitamic acid are dissolvedin water, for example, to a solution. Into this solution there is thenintroduced, at room temperature, 3.354grams of calcium carbonate, whichrepresents'a slight deflciency over the theoretical. The reaction .isconducted in the cold so that the CO2 formed in the reaction is kept insolution. The calcium cevitamate is passed cold through the Berkfeldfilter and filled in ampules in an inert atmosphere, preferably of C02.An atmosphere of carbon dioxide is especially advantageous as the gasappears to increase the normally high solubility of the salt in water,thereby enabling solutions of higher concentration to be obtained as thefinal product. To obtain a solid product, the solution is evaporated,preferably under vacuum in the cold. This product may likewise bepackages in an inert atmosphere and as already indicated, when preparedin tablet form, it may be given a gas-impervious coating, although theproduct may be prepared also in uncoated or unstabilized form.

The amount of water can, of course, be varied within wid limits. I havefound that calcium carbonate yields a clear solution of calciumcevitamate when reacted with cevitamic acid, and similar results areobtained with calcium hydroxide. Calcium gluconate and phosphate, on theother hand, do not give as clear solutions, although they may, ifdesired, be used.

Example 2 1.8 grams cevitamic acid (about .01 mol) are dissolved in 20cc. glycerol and 10 cc. N NaOH. To this are then added under stirringand cooling 35 cc. NNaOH and 22.5 cc. of aqueous Bi(NOa):5H2O(containing 35 mol) in the following order:

B10103) :5Ha0

In this way the solution is always kept alkaline until the finaladdition of the B10103) a. The orange-colored precipitate iscentrifuged, and then washed four times with distilled water bycentrifugation. The moist precipitate weighing approximately 5 g. whendry (theory 5.5 g.) is suspended in 100 cc. 50% glycerol and 5N NaOH isdropped in under stirring until a faint cloudiness persists. Thesolution is filtered through a filter cell and to the filtrate 2.5 cc.NazSO: solution (containing 250 mg.) are now added to stabilize it andit is brought down to pH around 7.6 with excess cevitamic acid. It isthen made up to 150 cc. with distilled water and bottled immediately.The preparation should contain approximately 20 mg. Bi per cc.

Example 3 1.8 g. cevitamic acid are dissolved in 10 cc. saturated saline(NaCl) solution. To this is added slowly under stirring 4.3 g. SbCladissolved in 20 cc. saturated saline solution. The acid solution iscooled with ice, and under stirring and cooling 12 cc. 5N NaOH saturatedwith salt are added. This leaves the solution still acid. Theprecipitate is centrifuged, and is then washed three times bycentritugation with distilled water. The moist precipitate weighing 4.8g. when dry (theory 4.9 g.) is now suspended in 100 cc. of 50% glycerolsolution and 5N alkali solution is dropped in under violent stirringuntil a faint ermanent cloudiness remains. The solution is filteredthrough a filter cell until clear, It should have a pH around 9.6. Thereare then added 2.5 cc. NazSOa (containing 250 mg.) to stabilize thesolution. If a lower pH is desired a little excess cevitamic acid canbeadded. The solution is then made up to 150 cc. and bottledimmediately. This solution should contain approximately 16 mg. Sb percc.

Example 4 20 g. (10 cc.) arsenlous chloride are dissolved in 50cc.'absolute alcohol and the solution shaken up with 1.8 g. cevitamicacid. Practically all the acid goes into solution which would not be thecase if the arsenlous chloride were absent. This indicates the formationof arsenic cevitamate. The arsenic cevitamate is less toxic thancurrently used arsenic preparations in the treatment of syphilis. The pHmay be adjusted with sodium hydroxide or other alkali to a value at'which the solution is stable and non-irritating on injection.

Example 5 suitable for injection. If desired. the solution may bebuflered with protein complexes, like gelatin. The amount of goldchloride employed is such that 1 cc. of the final solution contains.

Example 6 A solution of 27.8 grams of FGSO4.7H2O in 60 cc. of water aretreated under stirring with a solution of 10.6 grams NaaCOb in 50 cc. ofwater. The precipitated ferrous carbonate is allowed to stand for anhourand is then separated from the supernatant liquid by centrifugation. Itis then washed three times with distilled water in the centrifuge. Themoist precipitate is then slowly added under stirring to 17.6 grams ofcevitamic acid dissolved in 100 cc. of water. The solution of ferrouscarbonate should be practically complete. The solution is then filteredand made up to 186 cc. To this solution there are added 2 grams ofsodium citrate, which acts as a stabilizer. The solution contains 2grains of ferrous cevitamate per cc. although any other suitableconcentration can be prepared. The dosage may be considered lower thanthe usual dosage for iron; for example, cc. of the solution. In place ofthe sodium citrate, catechol and chlorophyl may be used as stabilizingagents in correspondingly small quantities.

When prepared in the absence of air, as in an inert atmosphere ofnitrogen or carbon dioxide, the solution is quite colorless and may beampuled as such.

Example 7 There is first formed the sodium salt of cevitamic acid, forexample by the mixing of 175 parts by weight of cevitamic acid in 400cc. of water with a concentrated solution of 40 parts by weight ofsodium hydroxide. The mixture should be stirred constantly and thesodium hydroxide is preferably added slowly. The solution of the acid inthe water may be aided by gentle heating. To this solution there isadded an approximately combining proportion of cupric chloride, forexample 67 parts by weight, either in a solid state or as a concentratedsolution in water. As the reaction proceeds, there is noted a change ofcolor of the solution to a light blue, the solution remaining clear. Thesolution is then warmed gently and an excess of sodium hydroxide isadded, causing precipitation of the copper compound of cevitamic acid.This is filtered and redissolved in water containing a small amount of asolubilizing or stabilizing agent, such as sodium citrate. cevitamatemay be prepared also by the reaction of cevitamic acid on freshlyprepared copper carbonate. The resulting solution may be evaporated todryness in a vacuum desiccator or added to a solution of ferrouscevitamate. In like manner, the cobalt cevitamate may be preparedthrough its carbonate and added to the solution of iron and copper, orevaporated to dryness in a vacuum desiccator. The iron, copper andcobalt cevitamate combination may be used dry in the form of tablets orcapsules or employed in the form of a solution, packaged in ampules forinjection. Especially where solutions are prepared, either in the courseof preparation or for marketing, the operations are preferably conductedin the absence of oxygen. The dosages may correspond to the knowndosages of iron and copper mixtures heretofore employed in the treatmentof anemia, both when admin- The copper istered parenterally because oithe greater emciencyof absorption, considerably smaller dosages ofthecevitamate compounds will be found eflective.

Although the copper and cobalt cevitamates have been described above asforming part of an anti-anemic preparation, it will be obvious thatthese compounds can be used for any therapeutic purpose for which copperand cobalt are indicated. i

To maintain the reduced state of the iron, as well as of the othermulti-valent metals whose cevitamic acid salts are prepared inaccordance with the present invention, various anti-oxidant stabilizerswhich ,are non-toxic in nature may be added to the solutions or even tothe solid preparations of the compounds. These anti-oxidants includecatechol, chlorophyl, various amines and amino compounds, includingglycine, acetanilide, and the like.

For the treatment of anemia and related diseases the iron, copper, andcobalt may be administered simultaneously in the form of theircevitamates; however, in certain cases it may be desirable to administeronly one of them at a time, or combination of only two of them.-

Where two or more of the metals are introduced simultaneously, only onemay be in the form of the cevitamate, the other or others being commonlyemployed compounds, such as the chloride, sulphate, or an organicderivative. Thus. iron cevitamate may be administered simultaneouslywith copper chloride and/or cobalt chloride, or with the sulphates ofcopper and/or cobalt. The copper and cobalt salts exert an activatingeflfect on the iron compound, and are used in smaller amounts than theiron. If desired, the cevitamates of copper and cobalt may beadministered without any iron, or the cevitamate of copper or cobalt maybe administered alone. In other words, in accordance with the invention,the material administered is one ccontaining the cevitamate radical, orthe radical of an organic derivative of cevitamic acid, and one or moreof the metals iron, copper and cobalt.

Example 8 A solution is made of 175 parts by weight of cevitamic acid inwater and to this are added slowly and with stirring parts of calciumgluconate. The originally clear solution gradually becomes cloudy and aprecipitate forms. The precipitate is filtered and is suspended in waterto which is added a small amount of sucrose. The mixture is heated to amoderate degree, whereupon the, precipitate dissolves. The amount ofwater employed is such that the mixture contains about 15% of calciumcevitamate. The resulting solution is then ready for use.

Bronchiolar reaction tests have shown that calcium cevitamate has anunusually strong strong histamine antagonism. Measurements made of theareas of bronchial tubes following and by mouth. However,

tions, particularly of staphylocci infections.

The bismuth, antimony and arsenic cevitamates are administeredparenterally, preferably intramuscularly. The dosage may amount to 20 to40 mg. of the metal once or twice weekly. They are all suitable for thetreatment of syphilis and pro tozoan diseases, like trypanosomiasis.

In syphilis, various known arsenic and bismuth preparations will notinfluence the Wassermann reaction in some cases. These "Wassermann fast"cases responded better to bismuth cevitamate than to known bismuth andarsenic preparations.

The product obtained may, if desired, be purifled in any known manner,for example, by fractional crystallization, by precipitation, by pouringinto organic water-miscible solvents in which they are insoluble, etc.Where sodium chloride is formed as a by-produet of the reaction, nopuriflcation is necessary since this salt aids in making the solutionisotonic. The solutions can, of course, be rendered isotonic by theaddition of sodium chloride or other salts.

The use of buffers in connection with solutions of the cevitamates isrecommended. The amounts of the buffer compound or compounds may bevaried at will and within wide limits. With certain compounds thesolubility is dependent upon the hydrogen ion concentration and suchbuflers tend to prevent changes of solubility of the compounds bypreventing changes of pH. Thus certain citrates and other alkali metalsalts of relatively weak organic acids aid in solubilizing ironcevitamate. Other solubilizing agents are the various carbohydrates suchas sucrose, dextrose, glucose, mannose, and other compounds of the sugartype.

Various organic acids, in addition to cevitamic acid can be employed foradjusting the pH to a lower alkalinity, but short of precipitation, asin the case of the arsenic, antimony and bismuth cevitamates. Amongthese acids are tartaric, citric, gluconic and other injectable organicacids. To bring the pH down from above 9 to 8, tartaric or citric acidis satisfactory; gluconic acid on the other hand may in such case causeprecipitation.

The buffers and anti-oxidants may be used in various combinations,provided that they form no precipitates in the cevitamate solutions.Thus sodium sulfite and sodium meta-bisulflte are suitable stabilizingagents for the various cevitamates,

- and particularly for the arsenic, antimony and bismuth compounds, andcan be used either alone or together with citrates, tartrates, sugars,etc. In certain cases organic acids like tartaric and citric acids andvarious combinations with salts may be used as buffer mixtures.

Where the alkali metal salt of cevitamic acid is reacted with anothercompound of another metal, such other compound may in general be thechloride, sulphate, nitrate, acetate or other inorganic or organicnon-toxic substance. In place of cevitamic acid the organic derivativesthereof such as the mono-acetone derivative can especially thesolutions, being stabilized against degenerative influences. Of course,the cevitamates may be marketed in the form of the "free acid and asuitable base of the therapeutic metal, packaged separately and designedto be mixed by the physician; or sodium cevitamate may be associated inthis fashion with a salt of the metal called for by the treatment, thetwo salts on mixingin water yielding the cevitamate of such metal. Thecevitamates may also be manufactured in the form of ternary andquaternary compounds, for example, as calcium glycerocevitamate, calciumglycerophosphate-cevitamate, and as other organic complexes.

I claim:

1. A therapeutic composition prepared for administration into the animalorganism, comprising the iron compound of cevitami acid, saidcomposition being indicated in the treatment of scurvy and anemia.

2. A therapeutic composition prepared for administration into theanimalorganism, comprising the copper compound of cevitamic acid, saidcomposition being indicated in the treatment of scurvy and anemia.

3. A therapeutic composition prepared for administration into the animalorganism, comprising a gold compound of cevitamic acid.

4. A preparation for the treatment of anemia, comprising a mixture ofiron and copper compounds, at least one of said compounds having thecevitamate radical.

5. A preparation for the treatment of anemia, comprising a. mixture ofiron, copper and cobalt compounds, at least one of said compounds havingthe cevitamate radical.

6. A composition prepared for injection into the animal organism,comprising a metal compound of cevitamic acid mixed with a stabilizingagent in the form of a non-toxic, inorganic salt having reducingproperties.

SIMON L. RUSKIN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,187,467 Stuart Jan. 16, 19402,073,207 Haworth Mar. 9, 1937 2,233,417 King et al Mar. 4, 19412,232,699 Engels Feb. 25, 1941 FOREIGN PA'IENTS Number Country Date397,886 Germany June 27, 1924 OTHER REFERENCES Herbert et al., J. Chem.Soc. (London), Sept. 1933, pages 1270-1288. (Copy in Sci. Libr.)

Szent. Gyorgyi, Biochem. Journ. (1928), vol. .2 p ges 1387-1409. (Copyin Sci. Libr.)

